Systematic Insight of Resveratrol Activated SIRT1 Interactome through Proximity Labeling Strategy

Abstract

SIRT1 functions by regulating the modification of proteins or interacting with other proteins to form complexes. It has been widely studied and found to play significant roles in various biological processes and diseases. However, systematic studies on activated-SIRT1 interactions remain limited. Here, we present a comprehensive SIRT1 interactome under resveratrol stimulation through proximity labeling methods. Our results demonstrated that RanGap1 interacted with SIRT1 in HEK 293T cells and MCF-7 cells. SIRT1 regulated the protein level of RanGap1 and had no obvious effect on RanGap1 transcription. Moreover, the overexpression of Rangap1 increased the ROS level in MCF-7 cells, which sensitized cells to resveratrol and reduced the cell viability. These findings provide evidence that RanGap1 interacts with SIRT1 and influences intracellular ROS, critical signals for mitochondrial functions, cell proliferation and transcription. Additionally, we identified that the SIRT1-RanGap1 interaction affects downstream signals induced by ROS. Overall, our study provides an essential resource for future studies on the interactions of resveratrol-activated SIRT1. There are conflicts about the relationship between resveratrol and ROS in previous reports. However, our data identified the impact of the resveratrol-SIRT1-RanGap1 axis on intracellular ROS.

Heart failure in patients is associated with downregulation of mitochondrial quality control genes

“…Reduced expression of MQC genes could be also a consequence of downregulation of multiple signalling pathways and transcription factors. For example, SIRT1, which was downregulated in our study, can activate several transcription factors related to mitochondrial biogenesis and mitophagy 24 …”

“…Despite unaltered PARGC1 expression, we observed reduced expression of key transcription factors, NRF1 that regulates expression of nuclear DNA‐encoded mitochondrial genes and TFAM that reguates expression of mitochondrial DNA‐encoded mitochondrial genes. SIRT1 and mTOR have ability to activate PGC‐1α, 23,24 regulate mitophagy and UPRmt 25–28 and we showed that they were downregulated in both ICM and DCM. Collectively, these data suggest reduced mitochondrial biogenesis in failing human hearts.…”

“…For example, SIRT1, which was downregulated in our study, can activate several transcription factors related to mitochondrial biogenesis and mitophagy. 24 The fold differences of mRNA expression between control and HF samples were relatively small and their biological impact could be of limited significance. On the other hand, HF is a chronic disease developing over years and cumulative effect of small changes in the expression of many genes over a long period of time may become a significant factor in the pathogenesis.…”

The Role of Nicotinamide Mononucleotide Supplementation in Psoriasis Treatment

“…NAD + acts as a substrate of sirtuin enzymes, which have dominant functions in inflammation, metabolism, gene expression, and immune response [18,48,49]. Each sirtuin family member (sirtuins 1-7, or SIRT 1-7) plays an important role in regulating and maintaining the stability of the internal environment of cells, and among these members, SIRT1 has become the most widely studied protein due to its diverse functions, strong deacetyla-tion ability, and high homology with the Saccharomyces cerevisiae transcription regulator Sir2 [50,51]. It has been reported that SIRT1 could increase mitochondrial biogenesis through activating PGC-1α via deacetylation [18,52,53], which plays a dominant part in regulating various mitochondrial proteins.…”